Glomerulonephritis, Nephritis, Chronic nephritis

1. What every clinician should know

Background

Glomerular diseases can be divided into those that primarily involve the kidney and those that are secondary to systemic disease such as diabetes or hypertension. The former is known as primary glomerulopathy and accounts for 80% of glomerular disease.

Glomerulonephritis (GN) is the inflammation of the glomeruli, which serve as the filtration units of the kidney. Glomeruli are made up of a bed of capillaries and basement membrane; inflammation interferes with the kidney’s function of blood filtration, causing leakage of protein and blood into the urine. Chronic inflammation can lead to scarring of the glomeruli, which in turn can cause impairment of renal function, elevated blood pressure and eventually the need for dialysis and transplantation.

Glomerular disease can cause proteinuria or hematuria, leading to nephrotic or nephritic syndromes, respectively. Nephrotic syndrome is defined by proteinuria of greater than three grams (g) per day, low serum albumin, edema and dyslipidemia. Nephritic syndrome is characterized by red blood cells and casts on urine microscopy, hypertension, renal insufficiency, mild proteinuria and edema. Glomerular disease may manifest with varying degrees of nephrotic and nephritic features.

Spontaneous remission in low risk group and in 30% of medium risk group

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BP control, steroids, ± immuno-suppressive agent§

40% response rate to steroids with complete remission

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Steroids, ± immuno-suppressive agent§

Poor response to therapy, high rate of ESRD

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Clinical observation, BP control, ± steroids

ESRD in 1/3 of patients

Goodpasture’s syndrome/anti-GBM disease

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Plasma exchange, steroids or immunosuppressive agent§

Good response with serum Cr<5 mg/dL and biopsy <50% crescents

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Symptomatic treatment

Typically self-limited

Minimal change disease (MCD)

Primarily seen in children under 6 years of age but can cause 30% of nephrotic syndrome in adults. Patients often present with acute onset nephrotic syndrome after an upper respiratory infection (URI). May also be seen as a result of non-steroidal anti-inflammatory drugs, Hodgkin’s and other lymphoproliferative diseases.

Membranous nephropathy (MN)

Most common cause of adult-onset nephrotic syndrome in the U.S. May also be seen with chronic hepatitis B infection, paraneoplastic syndromes and rheumatologic disorders.

Focal segmental glomerulosclerosis (FSGS)

Most common cause of idiopathic nephrotic syndrome in African-Americans. May also be seen as a result of obesity, hypertension, sickle cell disease and HIV.

Membranoproliferative glomerulonephritis (MPGN)

Three types present and differentiated by pathophysiology. MPGN typically occurs in older children and young adults and may present as nephrotic syndrome with minimally decreased renal function in 35%, nephritic syndrome in 35%, as chronic progressive GN in 20% or as a rapidly progressive variant with renal failure. Systemic hypertension is common and may be severe at time of presentation. Complement levels are typically low.

Immunoglobulin A nephropathy (IgAN)

Most common primary glomerular disease worldwide. The male to female ratio in the U.S. is 6:1. 40-50% of patients present with painless macroscopic hematuria at the time of infectious illness such as pharyngitis and the hematuria may last for 24 hours to 1 week after onset. 30-40% of patients may present with microscopic hematuria and mild proteinuria. Fewer than 5% have nephrotic range proteinuria.

Goodpasture’s syndrome (GPS) and anti-GBM disease (GBM)

Characterized by antibodies against the glomerular basement membrane. GMB is seen in one third of patients that have only kidney involvement and two thirds have both kidney and lung involvement (GPS). Presenting symptoms for GPS may include shortness of breath, cough or hemoptysis along with malaise, weight loss or fever. Pulmonary hemorrhage may precede renal involvement by years or occur after the GN diagnosis. Nephritic syndrome is common while nephrotic proteinuria is uncommon.

Poststreptococcal glomerulonephritis (PSGN)

May occur 2-3 weeks following a streptococcal pharyngitis or impetigo skin infection. The infection stimulates overproduction of antibodies that eventually deposit in the glomerulus, causing damage. It most commonly affects young children, although it can be seen in all ages. The episode is usually self-limiting. Typically presents with gross hematuria, nephrotic or subnephrotic proteinuria, edema and severe hypertension. Low C3 levels and normal C4 levels are common and anti-streptolysin O (ASO) titers are often elevated if the preceding infection was streptococcal pharyngitis.

Rapidly progressive glomerulonephritis (RPGN)

Considered a true medical emergency, and any of the nephritic syndromes could lead to RPGN. Small-vessel vasculitides and GBM/GPS are especially prone to cause RPGN. RPGN is subdivided into immune complex-mediated, pauci-immune (ANCA-associated), and anti-GBM disorders based on immune-fluorescence microscopy of the glomerulus.

Pregnancy in a woman with primary glomerulonephritis

Chronic renal conditions are relatively uncommon in pregnant patients, with a reported incidence of 3 in 10,000. Acute GN occurs in one in 40,000 pregnancies. There is an increased risk of perinatal loss associated with acute GN, as well as risk of worsening renal impairment and progression to ESRD.

Risk Factors for GN

Primary glomerulonephritis may be genetic or occur as a result of infection, drug effect, autoimmune response, or it may be idiopathic.

2. Diagnosis and differential diagnosis

A. Establishing the diagnosis

Evaluation of patients presenting with the above clinical features should include thorough history-taking, including infection and travel history, past medical and family history, and medication use history.

Signs and symptomsof renal disease, even if preexisting, may often manifest for the first time during pregnancy. It is sometimes difficult to distinguish among primary renal disease and preeclampsia. In one study of 86 women with severe hypertension, severe proteinuria or both during pregnancy, underlying renal disease was confirmed by postpartum renal biopsy in 22% of cases. The best predictor of underlying disease was the onset of severe hypertension and/or proteinuria before 30 weeks gestation and the most common condition was immunoglobulin A nephropathy (63%).

In women known to have a primary GN, laboratory evaluation at the time of antenatal care registration should include: a complete blood cell count, blood urea nitrogen and serum creatinine levels, lipid panel, serum albumin level, urinalysis and urine culture. A 24-hour urine collection for baseline protein and creatinine clearance quantification should also be obtained. While proteinuria may be assessed by urine dipstick or protein/creatinine ratio as well, the gold standard continues to be the measurement from a 24-hour urine collection.

In pregnant women with no prior renal diagnosis but who are suspected of having acute GN, urine microscopy should be performed to evaluate for presence of casts. C3 and C4 complement levels should be checked in evaluation of nephritic syndromes. ANA and anti-double stranded DNA titers may also be obtained to assess for lupus nephritis. An ANCA screen may be performed to evaluate for possible vasculitis-associated renal impairment. Renal ultrasound imaging should be obtained to evaluate anatomy and for signs of obstruction or infection.

Kidney biopsy may be indicated in the setting of worsening kidney function and no other explainable etiology. Renal biopsy is typically recommended in a highly selected group of women: pregnant women who are less than 28 weeks gestation with no prior history of renal disease that are found to have unexplained deterioration of renal function or symptomatic nephrotic syndrome. A biopsy in these situations would not only provide important diagnostic information but guide use of corticosteroids.

After 28 weeks gestation, early delivery can be considered and must be weighed against worsening renal status and the impact of that on patient and fetus. Renal biopsy may then be performed postpartum if renal function and proteinuria do not improve.

Pregnant women with a chronic condition, such as diabetes mellitus or systemic lupus erythematous (SLE), should be evaluated for underlying renal dysfunction prior to conception or early in pregnancy. They should be followed closely during pregnancy, especially if there is baseline renal impairment, for signs of worsening renal function.

B. Other possible diagnoses

In addition to GN, renal insufficiency in pregnancy may result from infection, congenital anomalies, obstruction or preeclampsia.

Urinary tract infections and pyelonephritis are more common in pregnancy and should be ruled out in the setting of worsening renal function or with signs and symptoms of infection. Diagnosis should be based on clinical picture, urinalysis, urine culture and occasionally with renal ultrasound. Significant azotemia is more likely to be seen with pyelonephritis in the pregnant patient compared to the nonpregnant patient.

Autosomal-dominant polycystic kidney disease (ADPKD) may also clinically manifest for the first time during pregnancy. ADPKD is rarely symptomatic before the third decade of life. Hypertension, flank pain, elevated serum creatinine and proteinuria may be seen in patients with ADPKD. Diagnosis is generally made with renal ultrasound.

Urinary tract obstruction may also result in renal dysfunction. Nephrolithiasis can generally be diagnosed with ultrasound. If pain is unremitting, infection is unresponsive to antimicrobial therapy, or there is complete obstruction with significant renal impairment, a ureteral stent or percutaneous nephrostomy should be considered.

Glomerulonephritis, especially nephrotic syndromes, may be easily mistaken for preeclampsia, as there is significant overlap in signs and symptoms. Furthermore, preexisting renal disease increases the risk of preeclampsia and therefore worsening primary renal disease may evolve into preeclampsia.

3. Management

In a nonpregnant patient, aggressive reduction in proteinuria is pursued with an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB). Dietary salt restriction and loop diuretics can be used to reduce edema. Hyperlipidemia should be managed with statins and, given the prothrombotic state created by a nephrotic syndrome, any patient with a previous history of thrombosis or severe hypoalbuminemia (less than 2.0 g/dL) should be anticoagulated.

In the preconception period, control of blood pressure and optimization of renal function are prudent prior to conception when possible. As ACEI and ARB are contraindicated in pregnancy, other antihypertensive agents considered to be safe in pregnancy such as labetalol, hydralazine or nifedipine should be used. While women with normal or near-normal renal function and well-controlled blood pressure generally have favorable outcomes with pregnancy, increasing degrees of renal impairment is associated with greater risks to the pregnancy and long term renal status.

Women with severe renal dysfunction (serum creatinine greater than 2.5 mg/dL) should be discouraged from conceiving given the high rates of preterm delivery (70%), preeclampsia (40%), and risk of postpartum deterioration of renal function potentially leading to ESRD (40%).

During pregnancy, the principles of primary GN management are similar to the non-pregnant state. Management includes frequent visits for monitoring BP and serial serum creatinine and urine protein measurements, controlling extreme elevations of blood pressure, prevention of congestive heart failure, maintenance of euvolemia and correction of electrolyte abnormalities. The outcomes for mother and pregnancy are dependent on the degree of renal impairment and blood pressure control before and during the pregnancy.

Thromboprophylaxis with low molecular weight heparin should be considered in pregnant women with proteinuria greater than 3g/24 hours given the increased thromboembolic risk of nephrotic syndrome in addition to the baseline elevated risk with pregnancy. It may also be advisable in pregnant women with proteinuria of 1-3g/24 hours and additional thromboembolic risk factors such as obesity, cigarette smoking, immobility or advanced maternal age (greater than 35 years). Prophylaxis should be continued for at least 6 weeks postpartum if proteinuria persists.

Early delivery may be indicated in the setting of worsening maternal status or with threatened fetal status. In the setting of acute renal deterioration after 28 weeks, delivery may be considered after consultation with a nephrologist to ensure all other therapeutic options have been exhausted and after careful consideration of the risks and benefits to the patient and fetus.

For primary GN, immunosuppressive therapies are often utilized (see below). Significant changes in medication regimens are not advisable; however, cyclophosphamide should be avoided in the first trimester and mycophenolate mofetil should not be used, as it has been shown to be associated with fetal malformations in humans. Prednisolone, azathioprine and hydroxychloroquine are considered safe to use during pregnancy. Potential risks of neonatal adrenal insufficiency and thymic hypoplasia exist with prednisolone, although they are unlikely with doses less than 15mg/day; risks of small for gestational age and dose-related myelosuppression in the fetus exist with azathioprine. Cyclosporine A and tacrolimus are safe but may be associated with increased risk of hypertension.

See Table I for treatment recommendations by histologic type.

MCD

MN

With normal serum creatinine at presentation, subnephrotic proteinuria and stable renal function for 6 months, patients are considered to be low risk. Symptomatic treatment of elevated blood pressure, edema and dyslipidemia is recommended in low-risk groups. Blood pressure control should include agents appropriate for use in pregnancy (use of ACEI or ARB first line in nonpregnant patients), while edema and dyslipidemia management should start with nonpharmacologic interventions such as tight stockings and lifestyle changes (statin treatment for dyslipidemia is contraindicated in pregnancy).

With normal serum creatinine, 4-8 grams protein/day and stable renal function for 6 months, patients are considered to be medium risk. Patients with persistent nephrotic syndrome are typically treated with corticosteroids alone or in combination with immunosuppressive or cytotoxic agents such as mycophenolate, cyclophosphamide or cyclosporine. High-risk patients have greater than 8g protein/day or impaired renal function and are treated with steroids and a cytoxic agent.

FSGS

Symptomatic control of elevated blood pressure is recommended and corticosteroid treatment is considered to be standard, with a minimum course of 12 months. If frequent relapse or steroid resistance occurs, cyclosporine or mycophenolate can be added.

MPGN

IgAN

In the pregnant patient, close clinical observation is advised if the patient does not have hypertension, renal insufficiency or more than 0.5g protein/day. In the setting of hypertension, blood pressure should be controlled with antihypertensive agents safe in pregnancy. Conservative therapy may be used in the nonpregnant patient with ACEI or ARB for renoprotective effects if patient does not have hypertension, renal insufficiency or more than 0.5g protein/day. If poor prognostic indicators are present, such as nephrotic range proteinuria and progressive renal failure, treatment with steroids should be pursued.

GPS/GBM

Treatment involves both plasma exchange and immunosuppressive agents such as steroids or cyclophosphamide.

PSGN

Typically self-limited and therefore management focuses on symptomatic treatment of edema and hypertension.

RPGN

Treatment involves first induction of remission followed by maintenance of therapy. Induction of remission generally requires aggressive therapy to control inflammation and prevent further damage with cyclophosphamide and pulsed IV methylprednisolone followed by daily oral steroids. Addition of plasma exchange may be beneficial for some patients. Following remission with 3-6 months of cyclophosphamide, azathioprine can be used for maintenance therapy.

4. Complications

Glomerulonephritis can lead to worsening renal function and even kidney failure. Acute renal insufficiency occurs over a short period of time and, although it can lead to permanent changes or even be life threatening, it typically resolves once the cause is treated. Chronic renal failure is the slow gradual loss of kidney function and if it goes unaddressed will progress to kidney failure requiring dialysis and/or transplantation.

Complications of nephrotic syndrome include infection, accelerated atherosclerosis, thrombosis and malnutrition. All patients with nephrotic syndrome are considered to be in a hypercoaguable state due to the urinary loss of coagulation inhibitors.

5. Prognosis and outcome

A. Effect of pregnancy on renal condition

In women with renal impairment at conception, a decline in renal function is often noted during the third trimester and may persist or worsen after delivery. There is some evidence that histopathologic type of primary GN may play a role in degree of deterioration of renal function. Hypertension and proteinuria also are risk factors in renal function decline.

In one multicenter study by Jones and Hayslett of 82 pregnancies in women with moderate or severe renal insufficiency (half due to chronic GN and half due to tubulointerstitial disease), 40% of women with moderate renal impairment (serum creatinine 1.4 mg/dL-1.9 mg/dL) had deterioration of renal function during pregnancy and 50% of these women had persistence of the deterioration after delivery. Sixty-five percent of women with serum creatinine 2.0 mg/dL or higher had worsening renal function during pregnancy and it persisted in the postpartum period in almost all of them, with 35% reaching ESRD. 45% of women with baseline serum Cr greater than 2.6 mg/dL will progress to ESRD within a few years after pregnancy.

The risk of progression to ESRD is thought to be low with MN but progressively higher with IgAN, MPGN and FSGS. A 1995 Lancet study by Jungers et al compared incidence of end-stage renal failure (serum creatinine greater than 0.5 mmol/L or need for dialysis) in 171 women who became pregnant to that in 189 women who did not become pregnant after clinical onset of histologically similar primary GN, with an average follow up of 15 years. They found that there was no difference in ESRF-free survival between pregnant women with normal renal function at conception compared to nonpregnant women. Histopathologic form of GN and hypertension, however, were noted to be important independent risk factors for progression to ESRF. The odds of progression to ESRF were progressively higher, as noted above, for IgAN, MPGN and FSGS.

B. Effect of renal disease on pregnancy

Among pregnant women with primary glomerular disease, the overall fetal loss rate is 21%, which includes a 13% perinatal death rate. Poor maternal and fetal outcomes are associated with impaired renal function, hypertension and nephrotic range proteinuria in the first trimester for all types of primary glomerulonephritis.

An Australian study by Packham et al looking at 395 pregnancies in women with biopsy-confirmed primary GN from 1962-1987 found fetal loss rate to be 26% and prenatal mortality rate to be 14%. Impaired renal function, early or severe hypertension and nephrotic range proteinuria were significantly associated with higher incidence of fetal loss, perinatal mortality and prematurity. These maternal complications were more common among pregnancies that occurred prior to primary GN diagnosis.

However, in a review by Vidaeff et al on renal conditions in pregnant women, a closer look by histologic type of glomerulonephritis reveals notable differences in pregnancy outcomes. With IgAN, the most commonly seen primary GN in pregnancy, the fetal loss was about 13% while in MN it was less than 10%. MPGN Type I, however, is associated with a fetal loss rate of about 25%. Type II MPGN is associated with a more favorable pregnancy outcome. The highest fetal loss rate (23 to 45%) as well as higher rates of intrauterine fetal growth restriction and preterm delivery (32%) is seen in women with FSGS. The overall rate of preterm delivery among women with primary GN is 19%.

Pregnancy outcome in women with renal disease is significantly dependent on degree of renal function impairment (Table II). Based on Vidaeff et al’s 2008 review of available literature, in women with chronic renal insufficiency fetal survival is only slightly diminished if the renal functional impairment is mild or moderate (serum creatinine less than 1.4 mg/dL, 1.4 mg/dL to 2.4-2.8 mg/dL, respectively) and irreversible renal function deterioration is uncommon.

Table II.

Fetal outcomes based on renal function impairment

Serum Creatinine (mg/dL)

Fetal Growth Restriction (%)

Preterm Delivery (%)

PerinatalMortality (%)

Mild

< 1.4

24

20

9

Moderate

1.4 to 2.4-2.8

35

36-61

7

Severe

> 2.4 – 2.8

43-57

73-86

36

With severe disease (serum creatinine greater than 2.4-2.8 mg/dL), however, fetal outcome is greatly affected, with the perinatal mortality rate four times that of those neonates born to women with mild or moderate disease. Perinatal morbidity doubles as a result of low birth weight and/or prematurity among neonates born to women with severe compared to mild or moderate renal disease.

Some argue that the associated complication of hypertension further places these pregnancies at risk. In the setting of primary GN, hypertension present at conception or early pregnancy increases fetal death rate two- to threefold. A 1997 study by Jungers et al reported a tenfold increase in fetal loss when hypertension was present at conception at comparable serum creatinine levels. Packham et al, however, found that in pregnancies of women with pre-existing treated hypertension the outcomes were comparable to those in pregnancies of normotensive women, possibly indicating the importance of controlling blood pressure prior to conception.

The risk of preeclampsia rises in women with preexisting renal disease and can increase to up to 80% of pregnant women with preexisting renal impairment and hypertension.

See Table I for primary glomerular disease-specific prognosis.

MCD

Worse prognosis in adults than children and typically relapses.

MN

Spontaneous remission common in low-risk group. Spontaneous remission within 3 years in 30% of medium-risk group. 10-year survival 65-85%. Subnephrotic proteinuria and female sex have a positive correlation with spontaneous remission.

FSGS

40% of patients respond to steroids with complete remission. Poor prognostic indicators: serum creatinine greater than 1.5 mg/dL and kidney biopsy showing interstitial fibrosis and more than 20% tubular atrophy. Resistance to treatment is correlated with progression to ESRD.

MPGN

High rate of ESRD as response to therapy poor; 10-year survival 50-60%.

IgAN

ESRD develops in one third of patients. Poor prognosis associated with hypertension, greater than 1.5 grams of protein/day, renal insufficiency or absence of macroscopic hematuria.

GPS/GBM

Good response to treatment is expected with a serum creatinine less than 5 mg/dL and a kidney biopsy showing less than 50% crescents.

PSGN

Prognosis is favorable in children although resolution may take months. In adults, persistent azotemia may result, in which case ACEI or ARB is indicated for renoprotection.

RPGN

ANCA-associated GN can rapidly progress to ESRD if untreated and in the setting of a systemic vasculitis there is a high 1-year mortality rate.

6. What is the evidence for specific management and treatment recommendations

(The authors of this study from Barcelona are experts in nephrology and obstetrics and gynecology. They prospectively followed the course of 66 pregnancies among 48 women with primary glomerular disease and compared the women’s clinical outcome at 1- and 5-year intervals to 36 nonpregnant women, matched by age, histological type and status of renal function. The study provides descriptive data on pregnancy outcome. The authors concluded that pregnancy does not adversely change the natural course of primary glomerular disease based on similar incidence of proteinuria, hypertension and renal failure.)

(This chapter on glomerular disease, written by nephrology experts from the Johns Hopkins School of Medicine, provides an encompassing overview of histological types of glomerular disease, including diagnostic findings and general management and prognosis guidelines.)

(This is a prospective cohort study to examine the risks of maternal and fetal complications in women with moderate to severe renal impairment.) (The authors followed 82 pregnancies in women with baseline serum creatinine of 1.4 mg/dL and found increased rates of complications related to worsening renal function, hypertension and obstetric complications, such as preterm delivery, growth restriction and infant mortality.)

(The authors are a group of nephrologists from France who undertook a retrospective case control study of 360 pregnant women with various histological forms of primary glomerulonephritis and normal renal function to evaluate for the occurrence of end-stage renal failure compared to nonpregnant women. Pregnancy was not found to affect the course of renal disease in women with normal renal function at conception.)

(This Australian retrospective case series reviews 395 pregnancies in women with primary glomerulonephritis and provides descriptive information on fetal and maternal outcomes as well as identification of risk factors for poor outcome.)

(The authors, who are maternal-fetal medicine experts, present this review of updated, evidence-based information to guide obstetric management of women with renal disease. The evidence they present supports the idea that the degree of renal functional impairment is a major predictor of pregnancy outcome and that presence of hypertension may further increase risks of a poor outcome.)